Following stroke, focused task-specific training for motor rehabilitation leads to superior functional outcomes compared to spontaneous recovery alone, yet residual disability remains a prominent issue. There is presently a resurgence of interest in the use of electric brain stimulation to facilitate motor recovery. The rationale is based on evidence supporting short-term behavioral changes correlated with and electrophysiological changes. If supplementary brain stimulation is to produce more robust and clinically meaningful outcomes, then a better understanding of the application parameters is required. We showed in 8 chronic stroke patients, that anodal tDCS delivered prior to robotic wrist training can significantly raised cortical excitability to the affected arm, accompanied with reduced intracortical inhibition, and lead to clinically meaningful improvements in wrist function over as little as six sessions. These results suggest that tDCS and voluntary sensorimotor cortex activation can co-exist, without interference, and may lead to enhanced motor memory acquisition. These results also raise critical questions about the temporal relationship of tDCS application and robotic training. Changes in motor cortex excitability resulting from tDCS are known to result from separate mechanisms during, and after the stimulation period, thus may have differential interactions with voluntary network activation, depending on when stimulation is delivered. The behavioral and electrophysiological consequences of manipulating the order of this combined therapy have not been previously tested. We hypothesize that tDCS coupled with physical therapy, can be more effective than therapy alone in promoting cortical plasticity and aiding recovery of motor function after stroke, if tDCS directly precedes therapy. We plan to use accepted TMS measures of cortical excitability, together with a novel twitch torque measure and motor control measures, to test the effects of tDCS delivered at different times in relation to an established motor encoding paradigm in chronic stroke patients. We predict that synaptic plasticity after-effects of anodal tDCS in M1, will enhance encoding of a motor pattern. The present proposal represents an innovative approach to understanding mechanisms of emerging stroke rehabilitation therapies, and thus relates directly to the aims of the present R21 FOA. PUBLIC HEALTH RELEVANCE: Stroke survivors are often left with residual motor dysfunction which despite the best known care, results in substantial personal, social and economic cost. Using non-invasive brain stimulation to augment effects of motor training in chronic stroke is an emerging technique, yet the mechanisms and optimal parameters remain unclear. Our findings will be useful to guide clinical trials for optimizing motor recovery in stroke, and may ultimately have broader application to other neurological disorders.